Method and apparatus for sample processing and injection

ABSTRACT

A sample processing/injection device for liquid chromatography comprises a septum at one end of the device, a processing chamber and injection needle disposed on a second end of the device. A fluid sample is transferred into the device by a transfer needle penetrating the septum of the device. The sample device may be positioned to a receiving component such as an injection valve of an instrument by movement of the transfer needle. The sample is injected into the receiving component through the injection needle of the sample processing/injection device through motive pressure supplied by the transfer needle. The sample processing/injection device reduces sampling steps and improves automation by performing sample processing and injection with a single device.

FIELD OF THE INVENTION

The present invention relates to sample processing and, moreparticularly, to a method and apparatus for automated sample handing,processing and testing utilizing a sample processing/injection device.

BACKGROUND OF THE INVENTION

The growth in medical and pharmaceutical research as well as diagnosticanalysis and testing has created a need for equipment and procedures forlow cost, high-speed sample collection and processing. Automatedequipment is available for filling and retrieval of samples from samplewells, vials, bottles and other containers.

Microplates comprising a plurality of sample wells provide a convenientmeans to handle and store samples. Automated equipment positionsmicroplates for sample filling, retrieving, and analysis. Despiteimprovements in sample handling equipment, many applications requiremanual labor when performing evolutions such as; preparing samplecontainers or vials, relocating sample containers, and passing samplefluids through process elements such as absorbents, adsorbents, filters,solid phase extraction mediums, or additive compound materials. Manualprocessing steps are usually required when sample numbers areinsufficient to justify design and building custom automated equipment.

Often the wells of microplates are used as the sample containers. Inother applications, vials or sample bottles are inserted into the wellsof microplates to contain the samples or testing fluids.

Certain types of testing such as chromatography, combinatorialchemistry, or high-throughput screening utilize processing of a sampleby a processing element such as solid phase extraction medium, a filter,or an adsorbent disk. The compounds of interest are recovered by passingsolvents through the processing element. This process requires multiplesteps that are difficult to automate, especially if the sample numbersare not sufficiently large to justify specialized equipment, containersand processes.

Sample processing devices such as those disclosed in U.S. Pat. No.6,959,615, hereby incorporated as reference, provide a means towithdraw, discharge, process and elute samples from sample vesselsincluding wells of microplates. While this is a significant improvementin reducing the number of steps and devices required for samplecollection, processing and testing, intermediate sample vessels arestill required between sample collection and sample injection into thefinal test instrument. Additionally, sample-to-sample exposure is asignificant threat to sample integrity and quality of the resultinganalytical data.

There exists a need for improved sample collection, processing andtesting devices to further reduce processing steps, improve speed andproductivity of sample testing evolutions, and perform serial processingon existing automated devices to improve data quality.

OBJECTS AND SUMMARY OF THE INVENTION

Therefore, an object of the present invention is to provide a sampleprocessing/injection device that can be used to collect, process andinject fluid samples.

Another object of the present invention is to provide a sampleprocessing/injection device that can be repositioned by movement of atransfer needle penetrating a septum of the device.

Another object of the present invention is to provide a sampleprocessing/injection device having an injection needle sealable with aninjection port of sampling instrument injection valve.

Another object of the present invention is to provide a sampleprocessing/injection device with an injection needle attachable by quickremovable connectors such as luer slip and luer lock fittings.

Another object of the present invention is to provide a sampleprocessing/injection device that can be placed in standard multi-welltrays.

Still another object of the present invention is to provide a sampleprocessing/injection device that is simple and low in cost.

The sample processing/injection device of the present invention is anelongated tubular structure having a sealing septum on one end and aninjection needle on the opposite end. The septum seals a conical needleguide and a reduced diameter through chamber having a close or tight fitwith a transfer needle of a manual or automated sampling apparatus. Thereduced diameter through chamber opens to a larger diameter processingchamber containing one or more processing elements such as frits,filters or solid phase extraction elements. The processing chamber is influid connection with the injection needle. In the preferredembodiments, an in-line fluid communication channel exists between thesealed septum end, reduced diameter through chamber, processing chamber,and injection needle.

In another embodiment, the sample device has a sealing septum on one endand a connector on the opposite end. The connector allows mechanicalattachment and fluid communication of the device with an injectionneedle. In the preferred embodiments, the connector is a quick-connecttapered connector such as a luer slip or a luer-lock connector. Thetaper portion of the connector may act as a drip tube for sample intakeor discharge from the sample processing/injection device.

The close or tight fit of the through chamber with a transfer needle anda through chamber length of at least 5 times the diameter of the throughchamber provides both engagement of the transfer needle and sampledevice and automatic alignment of the device with the transfer needle.The good alignment provided by the fit allows precision movement andplacement of the device utilizing only the transfer needle, simplifyinginstrument design and construction and speeding automated sampling. Forexample, the device may be transferred to the injection port of atesting machine and the injection needle sealed with the injection portby positioning of the transfer needle alone.

The combination of a luer slip or luer lock connector allows use of asmall diameter injection needle compatible with low volume testinginjection ports and a larger diameter drip tube portion for fast sampletransfer with the injection needle removed. The design also allows useof the connector as a drip tube for fast elution, intake or discharge ofsample or wash fluids into our out of the sample device.

The sample processing/injection device with both a drip tube and aninjection needle connectable with a quick-connect/disconnect connectorallows a number of sampling operations especially suitable forautomation. These operations and procedures include: intake ordischarging sample or wash fluids quickly into or out of the sampledevice using the drip tube integral with the connector, or withdrawingor injecting a sample or wash fluid via an injection needle attached bythe connector; moving and precise positioning the device with or withoutan injection needle by movement of a transfer needle inserted into theseptum and reduced-diameter through chamber of the sample device;attaching or removing the injection needle to/from the device bymovement of the transfer needle inserted into the septum andreduced-diameter through chamber of the sample device and injection ofsample fluid into a sample valve by an injection needle attached to thesample device, the positioning and injection needle penetrationaccomplished by movement of the transfer needle inserted into the septumand reduced-diameter through chamber of the sample device.

These and many other operations are made possible by transfer needleengagement and alignment features of the device and the combination driptube and injection needle connector of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features, aspects and advantages of the presentinvention will become better understood with regard to the followingdescription, appended claims and accompanying drawings where:

FIG. 1 is cross section elevation drawing of a prior art sampleprocessing device;

FIG. 2 is cross section elevation drawing of a sampleprocessing/injection device having an injection needle fixed to aremovable bottom end cap;

FIG. 2A is a detail cross section drawing of the sealing portion of theinjection needle of FIG. 2;

FIG. 3 is cross section elevation drawing of another embodiment of asample processing/injection device having an injection needle attachedto a bottom end cap of the device by a tapered connector such as a luerslip connector;

FIG. 4 is cross section elevation drawing of another embodiment of asample processing/injection device having an injection needle attachedto a bottom end cap of the device by a luer lock connector;

FIGS. 5A-5I are schematic drawings of process steps showing use of thesample processing/injection device through engagement of a transferneedle with the device to engage the injection needle of the device, tomove the device, to transfer sample to a receiving component and toremove the device from the transfer needle portion.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 is a cross section drawing of a prior art sample processingdevice 100 for retrieving, processing and discharging samples. Thedevice utilizes a penetrable septum 103, a conical needle guide 105, areduced diameter through chamber 107, a processing chamber 109 and adrip tube 111. A top cap, such as a crimp cap 113 secures septum 103 toa body portion 115 of the device. Cap aperture 113A provides access of aneedle (not shown) into the device. Sample processing elements such asfilters or frits 117A, 117B provide sample addition, subtraction,filtering, or other processing functions as known in the art. Bottom cap119 provides a means to insert, remove or replace processing elements117A, 117B in the device. Drip tube 111 provides sample collection from,or discharge into, a sample vessel or container.

FIG. 2 is a cross section drawing of an improved sampleprocessing/injection device capable of direct sample injection by use ofa needle such as injection needle 201 attached to bottom cap 219 ofprocessing/injection device 200. The construction and functions ofseptum 103, needle guide 105, reduced diameter through chamber 107,sample processing chamber 109, cap 113, body 115 and sample processingelements 117A, 117B is similar to that of FIG. 1. In the preferredembodiments, the device is made of a polymeric material such aspolyethylene, polypropylene, or polytetrafluoroethylene.

In the preferred embodiments, injection needle 201 is a metal needlehaving a length, diameter and end treatment suitable for samplecollection from a well, or penetration into a septum such as septum 103of another vessel or processing device. Needle 201 may have a formedseat surface 202 such as a beveled seat surface 203 of FIG. 2A forseating in other sample receiving apparatus such as sample injectionvalves of a liquid chromatography instrument as described later. Instill other embodiments, needle 201 may be angled for improved septumpenetration, or it may have a side opening for other applications.

In the preferred embodiments, needle 201 comprises a blunt end as shownin FIG. 2 and is sized for processing small sample volumes. In onepreferred embodiment, needle 201 diameter is selected to form a closefit tolerance with reduced diameter through chamber 107 to allow seriesconnection of the devices. In another embodiment, needle 201 diameter isselected to form a tight or slight interference fit with reduceddiameter through chamber 107 to allow positioning of one device byanother device.

Needle 201 may be attached to bottom cap 219 of device 200 by press fit,co-molding, or use of mechanical engagement elements such as threads ormechanical joints. In still other embodiments, welding, bonding oradhesives may be used.

In the preferred embodiments, bottom cap 219 is removable from body 115of the device to allow for insertion, removal or changing of processingelements 117A, 117B, and to allow changing of needle 201. Cap 219 mayform an interference, press fit with body 115, forming a liquid seal atseal portion 204. In other embodiments, bottom cap 219 may utilize snapfittings or other mechanical fittings known in the art. In still otherembodiments, bottom cap 210 is permanently attached to body 115.

FIG. 3 is a cross section drawing of another embodiment 300 of thesample processing/injection device of FIG. 2 having a removable needleportion 303 attached to bottom cap 319 of the device. In the preferredembodiments, needle portion 303 comprises a female interference taperfitting or luer slip fitting 305 which form an interference fit with acomplementary male luer slip fitting 307. In the preferred embodiments,male luer fitting 307 also functions as a high capacity drip tube onbottom cap 309.

Injection needle 301 is similar to needle 201 of FIG. 2 and is attachedto body 311 of needle portion 303 by press fit, snap fit, threadedconnection or other means known in the art. In the preferredembodiments, the diameter of bottom cap opening 308 is greater than theopening of injection needle 301 to allow fast sample transfer time withneedle 301 removed. Other components of device 300 are similar to thoseof FIG. 2.

FIG. 4 is a cross section drawing of another embodiment 400 of thesample processing/injection device of FIG. 2. Device 400 differs fromthat of the embodiment of FIG. 3 in that needle portion 403 incorporateslocking threads 415 that engage complementary locking threads such asluer lock threads 417 of bottom cap 419 to securely retain needleportion 403 to bottom cap 419. Other components of device 400 aresimilar to those of the earlier embodiments. In still other embodiments,other connector means such as snap fittings or compression fittings maybe used to attach the injection needle to the bottom cap or body of thedevice.

FIGS. 5A-5L show a preferred embodiment of a method of utilizing thesample processing/injection device to reduce processing steps andimprove productivity during sample processing and testing.

FIG. 5A is a schematic diagram of two sample processing/injectiondevices 300A, 300B disposed in wells of a standard multi-well sampletray 501 and accessed by a needle such as transfer needle 503 of anautomated processing instrument 502. In the preferred embodiments,reduced diameter through chamber 107 is selected to form a close fit orslight interference fit with transfer needle 503 and the reduceddiameter through chamber comprises a length of at least 5 times thediameter of the chamber to provide alignment of transfer needle 503 anddevice 300A. A tight or slight interference fit also provides sufficientgrip between needle 503 and the device to allow handling and precisemovement and positioning of the device with needle 503. In the preferredembodiments, a close tolerance fit is less than 0.005 on the diameter.In the preferred embodiments, a slight interference fit is less than0.005 on the diameter.

Needle guide 105 provides guidance for needle 503 during insertion ofthe needle as shown by arrow 505. Needle stop 507 provides control ofinsertion depth as shown in the needle-inserted position shown inphantom lines.

FIG. 5B is a schematic diagram of device 300A withdrawn vertically indirection 505A from well 501A by the interference fit of needle 503 andchamber 107. In the preferred embodiments, the length of chamber 107 ischosen to be at least 5 and preferably at least 10 diameters of chamber107 in order to provide axial alignment for precision placing of device300A.

FIG. 5C is a schematic diagram of device 300A withdrawn from well 501Aand being displaced horizontally in direction 505B to another processinglocation by needle 503 of the automated processing instrument.

FIG. 5D is a schematic diagram of device 300A positioned verticallyabove needle portion 303A in well 521A of tray 521. Device 300A ispositioned vertically downward in the direction of arrow 505 by needle503 of the automated processing instrument. As needle 503 positionsdevice 300A downward, male luer slip fitting 307 of bottom cap 319engages to form an interference fit with female luer slip fitting 305 ofneedle portion 303A as shown in FIG. 5E. Needle stop 507 of needle 503provides the interference fit insertion force and ledge 522 of well 521provides a reaction structure to accomplish the secure attachment ofneedle portion 303A to device 300A.

FIG. 5E is a schematic diagram of device 300A with needle portion 303Aattached positioned vertically upwards in the direction of arrow 505A byneedle 503 of the processing instrument.

FIG. 5F is a schematic diagram of device 300A with needle portion 303Aattached positioned horizontally in the direction of arrow 505B byneedle 503 of the processing instrument.

FIG. 5G is a schematic diagram of device 300A positioned verticallyabove a sample injection port such as injection port 541 of sampleinjection valve 543 and being positioned vertically downward in thedirection of arrow 505 by needle 503 of the automated processinginstrument. As needle 503 positions device 300A downward, valve-seatingsurface 302 of needle 301A engages injection valve seat 545 as shown inFIG. 5H. Needle stop 507 of needle 503 provides the injection valveseating insertion force against seat 545 to accomplish the necessarysealing of device 300A to injection valve 543. The accomplishment ofthis step allows injection of sample volume directly from sampleprocessing/injection device 300A into injection valve 543 for instrumentprocessing.

FIG. 5 I is schematic diagram of device 300A with needle portion 303Aattached positioned vertically upwards in the direction of arrow 505Aand horizontally in the direction of arrow 505B by needle 503 of theprocessing instrument.

FIG. 5J is a schematic diagram of device 300A positioned verticallyabove a sample device receiving component such as multi well tray 561and being positioned vertically downward in the direction of arrow 505by needle 503 of the automated processing instrument. As needle 503positions device 300A downward against device support surface 563 oftray 561 a device retaining element 565 is inserted by the processinginstrument as shown in FIG. 5K. Upon withdrawal of needle 503 in thedirection of arrow 505A, retaining element 565 retains device 300A inwell 561A. The interference fit of needle 503 in reduced diameterthrough chamber 107 is overcome by the upwards motion of needle 503 andprovides automated separation of device 303A and needle 503 as shown inFIG. 5L.

Although the process steps of FIGS. 5A-5L are shown for the embodimentof FIG. 3, similar process steps can be used for other deviceembodiments. For example, the fixed needle 201 attachment of FIG. 2would eliminate the necessity of steps 5D and 5E. The embodiment of FIG.4 would require an additional step of rotation of needle portion 403 inorder to secure or unlock needle portion 403 from bottom cap 419. Instill other embodiments, the female taper portion of the connectors ofembodiments 300 and 400 allow sample intake and elution directly fromthe device, similar to drip tube 111 of FIG. 1. In still otherembodiments, sample is withdrawn or discharged by needle 503 during anyof the process sequences shown in FIGS. 5A-5L.

Although the description above contains many specifications, theseshould not be construed as limiting the scope of the invention butmerely providing illustrations of some of the presently preferredembodiments of this invention. Thus the scope of the invention should bedetermined by the appended claims and their legal equivalents, ratherthan by the examples given.

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 12. A method for testing samples, the method comprising thesteps: penetrating a septum of a sample processing/injection device witha first injection needle, the processing/injection device comprising theseptum at a first end portion of the device, a reduced diameter throughchamber sized for a close tolerance or slight interference fit with thefirst injection needle, a processing chamber comprising a processingelement, and a second injection needle at a second end of the device,the reduced diameter through chamber, the processing chamber, and thesecond injection needle in line and in fluid communication with theseptum; transferring a sample into the processing/injection deviceutilizing vacuum or pressure of the first injection needle as a motiveforce for transferring the sample; physically repositioning the sampleprocessing/injection device to a sample processing location by movementof the first sample injection needle so that the second injection needleof the sample processing/injection device is positioned in a samplereceiving component at the sample processing location; and utilizing thefirst injection needle to inject the sample into sample receivingcomponent through the second injection needle.
 13. The method of claim12 wherein the reduced diameter through chamber comprises a length of atleast 5 diameters of the through chamber and forms a close fit or slightinterference fit with the first injection needle.
 14. The method ofclaim 12 wherein the sample receiving component is a sample injectionvalve of a liquid chronograph instrument, and the second injectionneedle is a sized to seal with an injection port seal surface of thesample injection valve.
 15. The method of claim 14 comprising anadditional step of removing the second injection needle of the sampleprocessing/injection device from the injection port of the injectionvalve by movement of the first injection needle.
 16. The method of claim15 comprising an additional step of removing the sampleprocessing/injection device from the first injection needle by restraintof the sample processing/injection device and movement of the firstinjection needle.
 17. The method of claim 12 wherein the sampleprocessing/injection device is assembled by engagement of a male taperfitting on a bottom end cap of the device and a complementary femaletaper fitting on an injection needle assembly of the device.
 18. Themethod of claim 17 wherein the engagement between the male taper fittingand female taper fitting is accomplished by movement of the firstinjection needle.